Apnea of prematurity is a common condition that is usually treated with methylxanthines. Methylxanthines are adenosine receptor blockers that have powerful influences on the central nervous system. However, little is known about the long-term effects of methylxanthines on the developing brain. In particular, it is not known whether methylxanthines have permanent adverse effects on sleep architecture and ventilatory control, resulting in an increased prevalence of sleep disorders such as insomnia and the obstructive sleep apnea syndrome (OSAS). Children who were born prematurely are at increased risk for neurobehavioral abnormalities. It is possible that these neurologic comorbidities are mediated, in part, through sleep disturbances that may result from methylxanthine exposure. This research proposal will take advantage of a unique cohort of ex-premature, 5-6 year old children who were randomized at birth to receive either caffeine or placebo, and are currently receiving detailed neurocognitive and behavioral assessments (the Caffeine for Apnea of Prematurity [CAP] trial). There is a time-based urgency to performing this study, as follow-up of the CAP cohort is in progress, and neurobehavioral assessments need to be performed in close proximity to the sleep assessments. The overall hypothesis is that methylxanthine use in preterm infants, while beneficial in the short term, results in longstanding abnormalities in the regulation of sleep, and breathing during sleep.
In Aim 1, we will determine the long-term effects of methylxanthine administration on sleep/wake patterns. Specifically, we will use actigraphy, sleep diaries and questionnaires to measure sleep in ex-premature 5-6 year old children who received either caffeine or placebo during the neonatal period. We hypothesize that children who received caffeine will have decreased sleep time, and increased prevalence of difficulties falling asleep and staying asleep, compared to controls.
In Aim 2, we will determine the long-term effects of methylxanthine administration on the prevalence of OSAS during childhood. Specifically, we will use ambulatory polysomnography to characterize breathing during sleep in ex-premature 5-6 year old children who received either caffeine or placebo during the neonatal period. We hypothesize that children who received caffeine will have an increased prevalence of OSAS.
In Aim 3, we will determine the contribution of sleep disruption, OSAS and methylxanthine administration to neurocognitive and behavioral abnormalities in ex-premature children. Specifically, we will determine the relationship between sleep time, OSAS and neurobehavioral measures (being obtained through the parent study) in ex-premature 5-6 year old children who received either caffeine or placebo during the neonatal period. We hypothesize that sleep disruption and OSAS will contribute to neurocognitive and behavioral abnormalities. These studies will help determine the long-term consequences of neonatal methylxanthine therapy, ultimately resulting in improved management of apnea of prematurity.

Public Health Relevance

Methylxanthines are used often in the neonatal intensive care unit to treat premature infants with apnea of prematurity. However, the long-term consequences of these drugs are unknown. This study will determine whether neonatal methylxanthine treatment results in long-term perturbations in sleep, breathing during sleep, and hence, neurocognitive and behavioral abnormalities.